A myriad of viral outbreaks have occurred throughout history, causing the deaths of hundreds of millions of people worldwide. Both DNA and RNA viruses are known and often transmitted by aerosols as well as by direct contact of contaminated surfaces. Viral infection may cause mild to severe symptoms in afflicted subjects, including humans. Accordingly, both prophylactic and therapeutic treatments remain a priority for development. However, both DNA and RNA viruses demonstrate rapid rate of mutation against therapeutic agents and as a result drug-resistant strains have become a concern for various viruses. New therapeutic agents are therefore needed to treat, cure and prevent viral infections.
Recent pandemic Ebola outbreaks in West Africa illustrate this need for treatment of viral hemorrhagic fevers (VHF), along with other viral infections. VHF are a collection of viral infections that are among the most feared human pathogens and thus an exemplary illustration for the need of broad spectrum antiviral compounds. VHF exist in four distinct families of RNA viruses: the Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae. The Filoviridae Ebola is prominent among these pathogens but there are representatives within the other families that present ongoing threats (for example, dengue, a flavivirus). For Ebola there are four distinct species: Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Ivory Coast ebolavirus (ICEBOV) (also known as Cote d'Ivoire ebolavirus (CIEBOV)), and Reston ebolavirus (REBOV). A new unnamed species of Ebola virus is suspected to be the causative agent of a recent outbreak of Ebola virus in Uganda. The highly contagious hemorrhagic fever virus originates from Africa and has a very high mortality rate. VHF viruses are transmitted by contact with bodily fluids from an infected subject and most often is fatal within a few days of hemorrhagic symptoms. These particular viruses attack endothelial cells of blood vessels, causing break down of blood vessels, allowing blood and serum to leak from the circulatory system.
Currently, there are no vaccines (except for yellow fever) or suitable drug candidates available to manage an uncontrollable outbreak and, as with the recent Ebola epidemic in West Africa only symptomatic measures are available for their treatment. As there are only a very limited number of possible therapeutics, for example, Ribavirin, a broad-spectrum antiviral agent with limited efficacy and extreme toxicity, few options are available for antiviral agents or vaccines for VHF. Because of limited access and the diversity of individual recipients' medical circumstances, vaccines pose issues that chemotherapeutic agents overcome. As a result, new therapeutic agents are needed to treat, cure, and prevent viral infections, including Ebola and other viral hemorrhagic fevers.
Naturally occurring neplanocin series of carbocyclic nucleosides or carbanucleosides are known as having the formulae shown in FIG. 1. The neplanocin compounds, namely neplanocin A, are known as having antiviral and antitumor activity as a result of the inhibition of S-adenosyl-L-homocysteine hydrolase (SAHase). SAHase catalyzes the interconversion of SAH into adenosine and L-homocysteine, and inhibition of this enzyme leads to an accumulation of SAH and a negative inhibition of cellular S-adenosyl-L-methionine (SAM)-dependent methyltransferase. Despite the potent enzyme inhibitory activity of neplanocin A, it has not been a clinically useful antiviral agent due to its potent toxicity to host cells. Another naturally-occurring carbocyclic nucleoside, aristeromycin, has been of interest due to its similar bioactivity. Various carbocyclic nucleosides have been synthesized as potential inhibitors of SAHase, although very few have been identified as potent inhibitors of SAHase, at least partly due to problems of the carbocycles to synthesize analogs to study. The carbocyclic nucleosides are thought to be synthetically a very challenging classification of nucleosides, requiring multiple, elaborate synthesis steps in order to introduce desired stereochemistry.
It has been identified that neplanocins offer a unique substitution pattern within the cyclopentenyl appendage. However the carbocyclic nucleosides are conformationally constrained by the alkene functionality or structural center. Changes to the C-1′, C-6′ isomer of neplanocin A disclosed pursuant to the present invention provide a framework for synthetic preparation of novel carbocyclic nucleosides in the neplanocin family of compounds. Accordingly, it is an objective of the claimed invention to develop enantiomers of 1′,6′-isoneplanocin employing the alkene and epoxide structural centers to make molecular modifications resulting in improved biological activity of the neplanocins, particularly neplanocin A.
A further object of the invention is to provide a synthesis framework for the enantiomers of 1′,6′-isoneplanocin.
A still further object of the invention is to provide methods of therapeutic or prophylactic antiviral treatment to complement vaccines, including employing the small molecule chemotherapeutic compounds disclosed herein. In particular, neplanocin derivatives are employed to treat or prevent DNA and/or RNA viruses, such as cytomegalovirus, measles, Ebola, norovirus, dengue, vaccinia or HBV. Preferably, compositions and methods of therapeutic or prophylactic antiviral treatment provide broad-spectrum antiviral activity.
Other objects, advantages and features of the present invention will become apparent from the following specification taken in conjunction with the accompanying drawings.